Recently, interest has been concentrated on various types of dementia such as cerebrovascular dementia, Altzheimer's disease, senile dementia, and the like, and the demand for effective methods for treating and preventing them are continuously increasing. It has been reported that a neurotoxic effect of cerebral excitatory amino acids, especially glutamate, which exhibits a neurotoxic effect following the binding to receptors, may be responsible for these diseases (Sinozaki, Gendaikagaku, 10: 38-44 (1987)). Prior to the present invention, many compounds had been provided with the intention of decreasing or eliminating the above aggravating effect of cerebral glutamate, including N-methyl-D-aspartic acid (hereinafter referred to as NMDA) channel antagonist such as MK-801 (H. Kato et al., Brain Res. 516: 175-179 (1990)]. However, they are not clinically applicable because of serious toxic effects. Therefore, safe compounds capable of preventing the massive release of cerebral glutamate have been required.
In the course of an investigation into dihydropyridine derivatives for the purpose of developing substances having Ca-blocking activity, a series of 4-aryl-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate derivatives were synthesized and tested for the binding affinity to Ca.sup.++ channels, coronary vasodilating effect and antihypertensive activity, and methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2,3-b]pyridine-5-c arboxylate (hereinafter, referred to as S-312) was found to be a potent vasodilating agent and also proved to have a potent antihypertensive and coronary vasodilating effect with lesser adverse reactions (U.S. Pat. No.4,703,051). Further study revealed that the major biological activities of said compound resides in the (+)-enantiomer with S configuration, i.e., methyl (+)-(4S)-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2,3-b]pyr idine-5-carboxylate (hereinafter, referred to as S-312-d), whose preparation is described in the Japanese Patent Publication (KOKAI) No.52890/1992.
Because of their selective Ca-blocking effect on vascular smooth muscle, S-312-d and S-312 exhibit antihypertensive activity, as well as peripheral, cerebral, and coronary vasodilating actions, which makes them useful in the treatment of circulatory diseases such as angina pectoris, hypertension, cerebrovascular dysfunction, arrhythmia, or the like. The useful effect on various cerebrovascular diseases is however not attributable to any specific properties of these compounds, but to the cerebral vasodilating effect common to Ca-blockers. Though one of ordinarily skill in the art might have thought that Ca-blockers were effective for preventing the cerebral apoplexy from occurring based upon their vasodilating action, he could hardly expect before the present invention that S-312-d was so effective on the ischemic neuronal cell damages consequent upon the cerebral apoplexy as well as the senile dementia.